Lack of Bioequivalence When Levofloxacin and Calcium‐Fortified Orange Juice Are Coadministered to Healthy Volunteers

Abstract

Chelation interactions between drugs/supplements that contain large amounts of multivalent ions and the fluoroquinolones have been known for quite some time. However, there has been a lack of taking this interaction into account when they may be coadministered with foods that have been fortified with amounts of multiple multivalent ions that equal or exceed many supplement products. A previous study demonstrated that 12 ounces of calcium-fortified orange juice significantly decreased the bioequivalence of a dose of ciprofloxacin. This study examined, in 16 healthy volunteers, whether 12 ounces of orange juice with and without calcium fortification would demonstrate the same chelation interaction with single doses of levofloxacin. The results of the study demonstrated that both types of juice decreased levofloxacin Cmax values by 14% to 18% and prolonged tmax values by approximately 50%, with calcium-fortified orange juice decreasing Cmax enough to lose bioequivalence as compared to the control arm (89% [78.1%, 99.8%]). Due to the lack of change in overall exposure, it is thought that rather than a chelation interaction, levofloxacin and components of the orange juices competed for intestinal transport mechanisms such as P-glycoprotein and organic anion-transporting polypeptides, which resulted in the discovered interaction. These results further confirm the need to adjust regulatory studies to include bioequivalence/bioavailability studies that contain fortified foods more than high-calorie/high-fat foods to better reflect current American consumption habits.

Lack of Bioequivalence of Levofloxacin When Coadministered with a Mineral‐Fortified Breakfast of Juice and Cereal

“…All plasma specimens were shipped frozen on dry ice to Emprexe Analytical, LLC (Buffalo, NY) for analysis of levofloxacin concentrations. A previously described reverse‐phase, high‐pressure liquid chromatographic (HPLC) assay was validated and used to quantitate levofloxacin in heparinized human plasma samples using difloxacin as the internal standard 7 . Linearity was observed over the calibration curve range of 0.100 to 10.0 μg/mL, and the assay had a limit of detection of 14.7 ng/mL (signal‐to‐noise ratio [S/N] = 5) for levofloxacin in plasma.…”

“…Study results demonstrated that when taken with 12 ounces of calcium‐fortified orange juice, the AUC of a dose of ciprofloxacin decreased by 38%, and the C max decreased by 41% as compared to when it was taken with an equivalent amount of water 5 . Although not to the same extent, more recent studies of similar design demonstrated that levofloxacin and gatifloxacin also lacked bioequivalence when coadministered with calcium‐fortified orange juice 6,7 . As quinolones are concentration‐dependent and/or exposure‐dependent killing antimicrobials, decreases in the C max and/or AUC have the potential to cause treatment failure and resistance development due to their pharmacokinetic and pharmacodynamic outcome predictors (C max :MIC, AUC:MIC) no longer being optimized 8,9 …”

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

“…Orange juice contains minor amounts of furanocoumarins and has little CYP3A4 inhibitory effect Won et al, 2010). It has been demonstrated that orange juice reduces the AUC of celiprolol (Lilja et al, 2004), atenolol (Lilja et al, 2005), fexofenadine (Dresser et al, 2002), ciprofloxacin (Neuhofel et al, 2002), and levofloxacin (Wallace et al, 2003). Because at least some of these drugs (e.g., fexofenadine, celiprolol) have been identified as substrates of OATPs expressed in the intestine, uptake inhibition of these transporters may be the cause for these interactions.…”

Influence of Dietary Substances on Intestinal Drug Metabolism and Transport

“…However, orange juice has been shown to reduce systemic exposure, significantly (by 22-83%), to fexofenadine [59], atenolol [145], and celiprolol [146]. Decreased mean AUC (up to 38%) also has been observed for the fluoroquinolones ciprofloxacin [147] and levofloxacin [148] with calcium-fortified and non-fortified orange juice. Any or all of these interactions could involve inhibition of enteric OATP by orange juice, as fexofenadine, levofloxacin, and celiprolol, have been shown to be substrates for OATP in vitro [59, 149, 150].…”